Clinical Efficacy and Adverse Effects of Bevacizumab in Combination with Chemotherapy for Metastatic Colorectal Cancer.

Objective: This study aims to investigate the efficacy of bevacizumab (BEV) in combination with chemotherapy for metastatic colorectal cancer (mCRC). Methods: A cohort of 121 patients diagnosed with mCRC and admitted to our hospital from May 2018 to October 2019 were selected for the study. The control group, comprising 64 patients, received chemotherapy alone, while the research group, consisting of 57 patients, underwent a combination of BEV and chemotherapy. Comparative analyses included an assessment of clinical outcomes, monitoring of tumor markers including Carcinoembryonic Antigen (CEA), Cancer Antigen 74-2 (CA74-2), and Carbohydrate Antigen 19-9 (CA19-9) before and after treatment, and a count of adverse effects during the treatment phase. A 3-year post-discharge follow-up was conducted to compare the survival prognosis between the two groups. Results: The research group exhibited a significantly higher objective response rate (ORR) and clinical benefit rate (CBR) compared to the control group (P < .05). Furthermore, CEA, CA74-2, and CA19-9 post-treatment levels were markedly lower in the research group (P < .05). No notable difference in the incidence of adverse reactions was observed between the two groups (P > .05). Importantly, the 3-year overall survival prognosis was superior in the research group (P < .05). Within the research group, patients treated with BEV combined with the XELIRI regimen chemotherapy demonstrated a higher CBR rate (P < .05). Conclusions: The combination of BEV and chemotherapy proves to be highly effective in treating mCRC, significantly enhancing the prognostic survival cycle of patients. This treatment modality holds promise for future clinical applications in managing patients with mCRC.

Preparation and characterization of furfural residue derived char-based catalysts for biomass tar cracking.

This study proposed an innovative strategy of catalytic cracking of tar during biomass pyrolysis/gasification using furfural residue derived biochar-based catalysts. Fe, Co, and Ni modified furfural residue char (FRC-Fe, FRC-Co, and FRC-Ni) were prepared by one-step impregnation method. The influences of cracking temperature and metal species on the tar cracking characteristics were investigated. The results showed that the tar conversion efficiency for all catalysts were improved with the cracking temperature increasing, the higher tar conversion efficiency achieved at 800 °C were 66.72 %, 89.58 %, 84.58 %, and 94.70 % for FRC, FRC-Fe, FRC-Co, and FRC-Ni respectively. FRC-Ni achieved the higher gas (H2, CO, CH4, CO2) yield 681.81 mL/g. At 800 °C, the catalyst (FRC-Ni) still reached a high tar conversion efficiency over 85.90 % after 5 cycles. SEM-EDS results showed that the distribution of Ni particles on the biochar support was uniform. TGA results demonstrated that FRC-Ni exhibited better thermal stability. XRD results indicated that there was no significant change in the grain size of Ni before and after the reaction. The FRC-Ni catalyst was reasonably stable due to its better anti-sintering and coke-resistant capabilities.

Effect of aggregation configuration of molecular fluorophore CZA on photoluminescence properties of carbon dots.

The effect of aggregation configuration of molecular fluorophore citrazinic acid (CZA) on the photoluminescence (PL) properties of carbon dots (CDs) has been investigated using first-principles method. The structural stability of all aggregates has been analyzed, and the results show that the most stable structures are J-type CZA aggregates with head-to-tail configurations and the CZA/CD aggregates are bonded by replacing H atoms on the CD edges with de-OH from the pyridine ring of CZA. The luminescent properties of CZA/CD aggregates are mainly affected by the binding modes and binding sites. When the sites belong to electron-donating groups, electron-withdrawing groups or sp2 domain, the PL spectra of CDs are shifted and the luminescent intensities are significantly enhanced. The results suggest that covalently bonded CZA/CD aggregates are responsible for the high fluorescence quantum yield of CD. Moreover, the distance between the centers of the two pyridine rings in H-type CZA dimers less than 3.5 Å is prone to π-π stacking, leading to fluorescence quenching of aggregates. The present work is helpful in understanding the effect of molecular fluorophores on the PL properties of CDs and provides theoretical guidance for the controllable synthesis of CDs.

Inhibition of neutrophil extracellular trap formation attenuates NLRP1-dependent neuronal pyroptosis via STING/IRE1α pathway after traumatic brain injury in mice.

Introduction: Increased neutrophil extracellular trap (NET) formation has been reported to be associated with cerebrovascular dysfunction and neurological deficits in traumatic brain injury (TBI). However, the biological function and underlying mechanisms of NETs in TBI-induced neuronal cell death are not yet fully understood. Methods: First, brain tissue and peripheral blood samples of TBI patients were collected, and NETs infiltration in TBI patients was detected by immunofluorescence staining and Western blot. Then, a controlled cortical impact device was used to model brain trauma in mice, and Anti-Ly6G, DNase, and CL-amidine were given to reduce the formation of neutrophilic or NETs in TBI mice to evaluate neuronal death and neurological function. Finally, the pathway changes of neuronal pyroptosis induced by NETs after TBI were investigated by administration of peptidylarginine deiminase 4 (a key enzyme of NET formation) adenovirus and inositol-requiring enzyme-1 alpha (IRE1α) inhibitors in TBI mice. Results: We detected that both peripheral circulating biomarkers of NETs and local NETs infiltration in the brain tissue were significantly increased and had positive correlations with worse intracranial pressure (ICP) and neurological dysfunction in TBI patients. Furthermore, the depletion of neutrophils effectively reduced the formation of NET in mice subjected to TBI. we found that degradation of NETs or inhibition of NET formation significantly inhibited nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 1 (NLRP1) inflammasome-mediated neuronal pyroptosis after TBI, whereas these inhibitory effects were abolished by cyclic GMP-AMP (cGAMP), an activator of stimulating Interferon genes (STING). Moreover, overexpression of PAD4 in the cortex by adenoviruses could aggravate NLRP1-mediated neuronal pyroptosis and neurological deficits after TBI, whereas these pro-pyroptotic effects were rescued in mice also receiving STING antagonists. Finally, IRE1α activation was significantly upregulated after TBI, and NET formation or STING activation was found to promote this process. Notably, IRE1α inhibitor administration significantly abrogated NETs-induced NLRP1 inflammasome-mediated neuronal pyroptosis in TBI mice. Discussion: Our findings indicated that NETs could contribute to TBI-induced neurological deficits and neuronal death by promoting NLRP1-mediated neuronal pyroptosis. Suppression of the STING/ IRE1α signaling pathway can ameliorate NETs-induced neuronal pyroptotic death after TBI.

[Screening, enzyme activity and genomic analysis of Paenibacillus silvae CH2]. / 类芽孢杆菌CH2çš„ç­›é€‰ã€é ¶æ´»æ€§åŠå ¨åŸºå› ç»„åˆ†æž.

Mangrove soil is a reliable source for screening cellulose-degrading bacteria due to the high diversity of microbes. To effectively utilize crop straw resources, a cellulolytic bacterium, Paenibacillus silvae strain CH2 was isolated from mangrove soil. We determined the carboxymethyl cellulose (CMC) and filter paper assay (FPA) activities of CH2 at different incubation times, NaCl concentrations, pH and temperatures, estimated the degradation efficiencies of rice and maize straw by CH2, sequenced and analyzed the whole genome of CH2. The results showed that along with the increases of incubation time, NaCl concentration, pH and temperature, the CMC and FPA activities increased first and then decreased . The highest CMC and FPA activities were observed at incubation time of 72-84 h, NaCl concentration of 6.0 g·L-1, pH of 7 and temperature of 36 ℃. Degradation of straw assays revealed that CH2 could effectively degrade rice and maize straw. At 0 g·L-1 NaCl (the control), the 10-day degradation rates of rice and maize straw were 30.4% and 47.0%, respectively. In the presence of 15 g·L-1 NaCl, the degradation rates were not significantly different from the control, indicating that CH2 had a high tolerance to salts. The whole genome of P. silvae CH2 was 6797325 bp, containing 6312 coding genes. P. silvae CH2 contained multiple genes encoding cellulose and hemicellulose degrading enzymes. These enzymes mainly belonged to the GH family, including endo-1,4-ß-xylanase, Xylan 1,4-ß-xylosidase, ß-glucosidase, and endoglucanase. The results indicated that the bacterium had the potential to be used in crop straw degradation.

Chromatin dynamics associated with seed desiccation tolerance/sensitivity at early germination in Medicago truncatula.

Desiccation tolerance (DT) has contributed greatly to the adaptation of land plants to severe water-deficient conditions. DT is mostly observed in reproductive parts in flowering plants such as seeds. The seed DT is lost at early post germination stage but is temporally re-inducible in 1 mm radicles during the so-called DT window following a PEG treatment before being permanently silenced in 5 mm radicles of germinating seeds. The molecular mechanisms that activate/reactivate/silence DT in developing and germinating seeds have not yet been elucidated. Here, we analyzed chromatin dynamics related to re-inducibility of DT before and after the DT window at early germination in Medicago truncatula radicles to determine if DT-associated genes were transcriptionally regulated at the chromatin levels. Comparative transcriptome analysis of these radicles identified 948 genes as DT re-induction-related genes, positively correlated with DT re-induction. ATAC-Seq analyses revealed that the chromatin state of genomic regions containing these genes was clearly modulated by PEG treatment and affected by growth stages with opened chromatin in 1 mm radicles with PEG (R1P); intermediate openness in 1 mm radicles without PEG (R1); and condensed chromatin in 5 mm radicles without PEG (R5). In contrast, we also showed that the 103 genes negatively correlated with the re-induction of DT did not show any transcriptional regulation at the chromatin level. Additionally, ChIP-Seq analyses for repressive marks H2AK119ub and H3K27me3 detected a prominent signal of H3K27me3 on the DT re-induction-related gene sequences at R5 but not in R1 and R1P. Moreover, no clear H2AK119ub marks was observed on the DT re-induction-related gene sequences at both developmental radicle stages, suggesting that silencing of DT process after germination will be mainly due to H3K27me3 marks by the action of the PRC2 complex, without involvement of PRC1 complex. The dynamic of chromatin changes associated with H3K27me3 were also confirmed on seed-specific genes encoding potential DT-related proteins such as LEAs, oleosins and transcriptional factors. However, several transcriptional factors did not show a clear link between their decrease of chromatin openness and H3K27me3 levels, suggesting that their accessibility may also be regulated by additional factors, such as other histone modifications. Finally, in order to make these comprehensive genome-wide analyses of transcript and chromatin dynamics useful to the scientific community working on early germination and DT, we generated a dedicated genome browser containing all these data and publicly available at https://iris.angers.inrae.fr/mtseedepiatlas/jbrowse/?data=Mtruncatula.

Evaluation of decompressive craniectomy in mice after severe traumatic brain injury.

Decompressive craniectomy (DC) is of great significance for relieving acute intracranial hypertension and saving lives after traumatic brain injury (TBI). In this study, a severe TBI mouse model was created using controlled cortical impact (CCI), and a surgical model of DC was established. Furthermore, a series of neurological function assessments were performed to better understand the pathophysiological changes after DC. In this study, mice were randomly allocated into three groups, namely, CCI group, CCI+DC group, and Sham group. The mice in the CCI and CCI+DC groups received CCI after opening a bone window, and after brain injury, immediately returned the bone window to simulate skull condition after a TBI. The CCI+DC group underwent DC and contused tissue removal 6 h after CCI. The mice in the CCI group underwent the same anesthesia process; however, no further treatment of the bone window and trauma was performed. The mice in the Sham group underwent anesthesia and the process of opening the skin and bone window, but not in the CCI group. Changes in Modified Neurological Severity Score, rotarod performance, Morris water maze, intracranial pressure (ICP), cerebral blood flow (CBF), brain edema, blood-brain barrier (BBB), inflammatory factors, neuronal apoptosis, and glial cell expression were evaluated. Compared with the CCI group, the CCI+DC group had significantly lower ICP, superior neurological and motor function at 24 h after injury, and less severe BBB damage after injury. Most inflammatory cytokine expressions and the number of apoptotic cells in the brain tissue of mice in the CCI+DC group were lower than in the CCI group at 3 days after injury, with markedly reduced astrocyte and microglia expression. However, the degree of brain edema in the CCI+DC group was greater than in the CCI group, and neurological and motor functions, as well as spatial cognitive and learning ability, were significantly poorer at 14 days after injury.

Social Support and Family Functioning during Adolescence: A Two-Wave Cross-Lagged Study.

The influence of social and family factors on adolescent mental health has been widely valued. Considering adolescents' family systems in a broader social context facilitates a better understanding of their mental health, which also has special significance in the post-epidemic era. The purpose of the present study was to explore the relationship between social support and family functioning during adolescence. Students from two middle schools in Fujian province, China, were recruited as participants. Seven hundred and fifty-four participants completed the questionnaire twice in six-month intervals. We constructed a cross-lagged model by using IBM SPSS AMOS 26.0 to test the relationship between these two variables. Social support and family functioning predicted each other in the girls, but not for the boys' sample. The results of this study suggested that the interaction between family and social factors and the possible gender differences should be considered when dealing with adolescents' mental health problems.

Chromatin Immunoprecipitation dataset of H3ac and H3K27me3 histone marks followed by DNA sequencing of Medicago truncatula embryos during control and heat stress conditions to decipher epigenetic regulation of desiccation tolerance acquisition.

Desiccation tolerance (DT) is one of the most important processes that seeds need to acquire during seed maturation because it will ensure survival until seeds have favourable conditions for germinating. Moreover, in the current climate warming context, heat stress and its impact on seed maturation and quality has been increasingly studied by the scientific community. Even if the transcriptomic changes enrolled in DT acquisition and seed heat stress response are fairly known, its epigenetic control has not yet been investigated. Medicago truncatula is a model legume for studying seed molecular mechanisms, which is known to display a delay in the acquisition of seed maturation mechanisms under heat conditions, except for desiccation acquisition. Our aim was to evaluate the role of two histone marks during embryo development under control and heat stress conditions on seed maturation processes, including the DT acquisition. These histone marks have either repressive (H3K27me3) or inducible (H3ac) effects on gene transcription, respectively corresponding to markers of packed and accessible chromatins. We identified all genomic regions bound to the H3K27me3 histones at four developmental stages and to the H3ac histones at the two earlier developmental stages during seed maturation, from seed filling to mature dry seeds, collected under optimal and heat stress conditions in the model legume, Medicago truncatula (reference genotype A17). A list of genes and promoters potentially linked to these two histone marks is reported and could provide clues about the epigenetic regulation of seed maturation between control and heat stress conditions, including the desiccation tolerance acquisition.

The probiotic effects of AB23A on high-fat-diet-induced non-alcoholic fatty liver disease in mice may be associated with suppressing the serum levels of lipopolysaccharides and branched-chain amino acids.

Alisol B 23-acetate (AB23A) is a natural triterpenoid isolated from Rhizoma alisamatis that has been widely used as a traditional Chinese medicine (TCM). Previous studies have documented the beneficial effect of AB23A on non-alcoholic fatty liver disease (NAFLD), but the functional interactions between gut microbiota and the anti-NAFLD effect of AB23A remain unclear. In this study, we investigated the benefits of experimental treatment with AB23A on gut microbiota dysbiosis in NAFLD with an obesity model. C57BL/6J mice were administrated a high-fat diet (HFD) with or without AB23A for 12 weeks. AB23A significantly improved metabolic phenotype in the HFD-fed mice. Moreover, results of 16S rRNA gene-based amplicon sequencing in each group reveled that AB23A not only reduced the abundance of the Firmicutes/Bacteroidaeota ratio and Actinobacteriota/Bacteroidaeota ratio, but regulated the abundance of the top 10 genera, including norank_f__Muribaculaceae, Lactobacillus, Ileibacterium, Turicibacter, Faecalibaculum, the Lachnospiraceae_NK4A136_group, unclassified_f__Lachnospiraceae, and norank_f__Lachnospiraceae. AB23A significantly reduced the serum levels of lipopolysaccharide and branched-chain amino acids, which are positively correlated with the abundances of Ileibacterium and Turicibacter. Moreover, AB23A led to remarkable reductions in the activation of TLR4, NF-κB, and mTOR, and upregulated the expression of tight junction proteins, including ZO-1 and occludin. These results revealed that AB23A displayed a prebiotic capacity in HFD-fed NAFLD mice.

Sigma-1 Receptor: A Potential Therapeutic Target for Traumatic Brain Injury.

The sigma-1 receptor (Sig-1R) is a chaperone receptor that primarily resides at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) and acts as a dynamic pluripotent modulator regulating cellular pathophysiological processes. Multiple pharmacological studies have confirmed the beneficial effects of Sig-1R activation on cellular calcium homeostasis, excitotoxicity modulation, reactive oxygen species (ROS) clearance, and the structural and functional stability of the ER, mitochondria, and MAM. The Sig-1R is expressed broadly in cells of the central nervous system (CNS) and has been reported to be involved in various neurological disorders. Traumatic brain injury (TBI)-induced secondary injury involves complex and interrelated pathophysiological processes such as cellular apoptosis, glutamate excitotoxicity, inflammatory responses, endoplasmic reticulum stress, oxidative stress, and mitochondrial dysfunction. Thus, given the pluripotent modulation of the Sig-1R in diverse neurological disorders, we hypothesized that the Sig-1R may affect a series of pathophysiology after TBI. This review summarizes the current knowledge of the Sig-1R, its mechanistic role in various pathophysiological processes of multiple CNS diseases, and its potential therapeutic role in TBI.

Genome-Wide Association Studies of Seed Performance Traits in Response to Heat Stress in Medicago truncatula Uncover MIEL1 as a Regulator of Seed Germination Plasticity.

Legume seeds are an important source of proteins, minerals, and vitamins for human and animal diets and represent a keystone for food security. With climate change and global warming, the production of grain legumes faces new challenges concerning seed vigor traits that allow the fast and homogenous establishment of the crop in a wide range of environments. These seed performance traits are regulated during seed maturation and are under the strong influence of the maternal environment. In this study, we used 200 natural Medicago truncatula accessions, a model species of legumes grown in optimal conditions and under moderate heat stress (26°C) during seed development and maturation. This moderate stress applied at flowering onwards impacted seed weight and germination capacity. Genome-wide association studies (GWAS) were performed to identify putative loci or genes involved in regulating seed traits and their plasticity in response to heat stress. We identified numerous significant quantitative trait nucleotides and potential candidate genes involved in regulating these traits under heat stress by using post-GWAS analyses combined with transcriptomic data. Out of them, MtMIEL1, a RING-type zinc finger family gene, was shown to be highly associated with germination speed in heat-stressed seeds. In Medicago, we highlighted that MtMIEL1 was transcriptionally regulated in heat-stressed seed production and that its expression profile was associated with germination speed in different Medicago accessions. Finally, a loss-of-function analysis of the Arabidopsis MIEL1 ortholog revealed its role as a regulator of germination plasticity of seeds in response to heat stress.

Different Functional Network Connectivity Patterns in Epilepsy: A Rest-State fMRI Study on Mesial Temporal Lobe Epilepsy and Benign Epilepsy With Centrotemporal Spike.

The stark discrepancy in the prognosis of epilepsy is closely related to brain damage features and underlying mechanisms, which have not yet been unraveled. In this study, differences in the epileptic brain functional connectivity states were explored through a network-based connectivity analysis between intractable mesial temporal lobe epilepsy (MTLE) patients and benign epilepsy with centrotemporal spikes (BECT). Resting state fMRI imaging data were collected for 14 MTLE patients, 12 BECT patients and 16 healthy controls (HCs). Independent component analysis (ICA) was performed to identify the cortical functional networks. Subcortical nuclei of interest were extracted from the Harvard-Oxford probability atlas. Network-based statistics were used to detect functional connectivity (FC) alterations across intranetworks and internetworks, including the connectivity between cortical networks and subcortical nuclei. Compared with HCs, MTLE patients showed significant lower activity between the connectivity of cortical networks and subcortical nuclei (especially hippocampus) and lower internetwork FC involving the lateral temporal lobe; BECT patients showed normal cortical-subcortical FC with hyperconnectivity between cortical networks. Together, cortical-subcortical hypoconnectivity in MTLE suggested a low efficiency and collaborative network pattern, and this might be relevant to the final decompensatory state and the intractable prognosis. Conversely, cortical-subcortical region with normal connectivity remained well in global cooperativity, and compensatory internetwork hyperconnectivity caused by widespread cortical abnormal discharge, which might account for the self-limited clinical outcome in BECT. Based on the fMRI functional network study, different brain network patterns might provide a better explanation of mechanisms in different types of epilepsy.

Antiepileptic Efficacy and Network Connectivity Modulation of Repetitive Transcranial Magnetic Stimulation by Vertex Suppression.

A core feature of drug-resistant epilepsy is hyperexcitability in the motor cortex, and low-frequency repetitive transcranial magnetic stimulation (rTMS) is a suitable treatment for seizures. However, the antiepileptic effect causing network reorganization has rarely been studied. Here, we assessed the impact of rTMS on functional network connectivity (FNC) in resting functional networks (RSNs) and their relation to treatment response. Fourteen patients with medically intractable epilepsy received inhibitive rTMS with a figure-of-eight coil over the vertex for 10 days spread across two weeks. We designed a 6-week follow-up phase divided into four time points to investigate FNC and rTMS-induced timing-dependent plasticity, such as seizure frequency and abnormal interictal discharges on electroencephalography (EEG). For psychiatric comorbidities, the Hamilton Depression Scale (HAM-D) and the Hamilton Anxiety Scale (HAM-A) were applied to measure depression and anxiety before and after rTMS. FNC was also compared to that of a cohort of 17 healthy control subjects. The after-effects of rTMS included all subjects that achieved the significant decrease rate of more than 50% in interictal epileptiform discharges and seizure frequency, 12 (14) patients with the reduction rate above 50% compared to the baseline, as well as emotional improvements in depression and anxiety (p < 0.05). In the analysis of RSNs, we found a higher synchronization between the sensorimotor network (SMN) and posterior default-mode network (pDMN) in epileptic patients than in healthy controls. In contrast to pre-rTMS, the results demonstrated a weaker FNC between the anterior DMN (aDMN) and SMN after rTMS, while the FNC between the aDMN and dorsal attention network (DAN) was greater (p < 0.05, FDR corrected). Importantly, the depressive score was anticorrelated with the FNC of the aDMN-SMN (r = -0.67, p = 0.0022), which was markedly different in the good and bad response groups treated with rTMS (p = 0.0115). Based on the vertex suppression by rTMS, it is possible to achieve temporary clinical efficacy by modulating network reorganization in the DMN and SMN for patients with refractory epilepsy.

Variation in the vulnerability of mice expressing human superoxide dismutase 1 to prion-like seeding: a study of the influence of primary amino acid sequence.

Misfolded forms of superoxide dismutase 1 (SOD1) with mutations associated with familial amyotrophic lateral sclerosis (fALS) exhibit prion characteristics, including the ability to act as seeds to accelerate motor neuron disease in mouse models. A key feature of infectious prion seeding is that the efficiency of transmission is governed by the primary sequence of prion protein (PrP). Isologous seeding, where the sequence of the PrP in the seed matches that of the host, is generally much more efficient than when there is a sequence mis-match. Here, we used paradigms in which mutant SOD1 seeding homogenates were injected intraspinally in newborn mice or into the sciatic nerve of adult mice, to assess the influence of SOD1 primary sequence on seeding efficiency. We observed a spectrum of seeding efficiencies depending upon both the SOD1 expressed by mice injected with seeds and the origin of the seed preparations. Mice expressing WT human SOD1 or the disease variant G37R were resistant to isologous seeding. Mice expressing G93A SOD1 were also largely resistant to isologous seeding, with limited success in one line of mice that express at low levels. By contrast, mice expressing human G85R-SOD1 were highly susceptible to isologous seeding but resistant to heterologous seeding by homogenates from paralyzed mice over-expressing mouse SOD1-G86R. In other seeding experiments with G85R SOD1:YFP mice, we observed that homogenates from paralyzed animals expressing the H46R or G37R variants of human SOD1 were less effective than seeds prepared from mice expressing the human G93A variant. These sequence mis-match effects were less pronounced when we used purified recombinant SOD1 that had been fibrilized in vitro as the seeding preparation. Collectively, our findings demonstrate diversity in the abilities of ALS variants of SOD1 to initiate or sustain prion-like propagation of misfolded conformations that produce motor neuron disease.

Supercharging Prions via Amyloid-Selective Lysine Acetylation.

Repulsive electrostatic forces between prion-like proteins are a barrier against aggregation. In neuropharmacology, however, a prion's net charge (Z) is not a targeted parameter. Compounds that selectively boost prion Z remain unreported. Here, we synthesized compounds that amplified the negative charge of misfolded superoxide dismutase-1 (SOD1) by acetylating lysine-NH3+ in amyloid-SOD1, without acetylating native-SOD1. Compounds resembled a "ball and chain" mace: a rigid amyloid-binding "handle" (benzothiazole, stilbene, or styrylpyridine); an aryl ester "ball"; and a triethylene glycol chain connecting ball to handle. At stoichiometric excess, compounds acetylated up to 9 of 11 lysine per misfolded subunit (ΔZfibril =-8100 per 103 subunits). Acetylated amyloid-SOD1 seeded aggregation more slowly than unacetylated amyloid-SOD1 in vitro and organotypic spinal cord (these effects were partially due to compound binding). Compounds exhibited reactivity with other amyloid and non-amyloid proteins (e.g., fibrillar α-synuclein was peracetylated; serum albumin was partially acetylated; carbonic anhydrase was largely unacetylated).

Amlexanox Enhances Temozolomide-Induced Antitumor Effects in Human Glioblastoma Cells by Inhibiting IKBKE and the Akt-mTOR Signaling Pathway.

Temozolomide (TMZ), as the first-line chemotherapeutic agent for the treatment of glioblastoma multiforme (GBM), often fails to improve the prognosis of GBM patients due to the quick development of resistance. The need for more effective management of GBM is urgent. The aim of this study is to evaluate the efficacy of combined therapy with TMZ and amlexanox, a selective inhibitor of IKBKE, for GBM. We found that the combined treatment resulted in significant induction of cellular apoptosis and the inhibition of cell viability, migration, and invasion in primary glioma cells and in the human glioma cell line, U87 MG. As expected, TMZ enhanced the expression of p-AMPK and amlexanox led to the reduction of IKBKE, with no impact on p-AMPK. Furthermore, we demonstrated that compared to other groups treated with each component alone, TMZ combined with amlexanox effectively reversed the TMZ-induced activation of Akt and inhibited the phosphorylation of mTOR. In addition, the combination treatment also clearly reduced in vivo tumor volume and prolonged median survival time in the xenograft mouse model. These results suggest that amlexanox sensitized the primary glioma cells and U87 MG cells to TMZ at least partially through the suppression of IKBKE activation and the attenuation of TMZ-induced Akt activation. Overall, combined treatment with TMZ and amlexanox may provide a promising possibility for improving the prognosis of glioblastoma patients in clinical practice.

RNA sequencing data for heat stress response in isolated medicago truncatula seed tissues.

Legumes are important crop species as they produce highly nutritious seeds for human food and animal feed. In grain legumes, sub-optimal conditions affect seed developmental timing leading to impairment of seed quality traits acquired during seed maturation. To understand the molecular mechanisms of heat stress response in legume seeds, we analysed transcriptome changes of three seed tissues (i.e. em bryo, endosperm and seed coat) at four developmental stages, during seed maturation, from seed filling to mature dry seeds, collected under optimal and heat stress conditions in the model legume, Medicago truncatula (reference genotype A17). The total RNA sequencing generated a dataset of 48 samples, representing more than 57 Gb fastq raw data. Mapping, quantification and annotation of the data were based on fifth release of Medicago truncatula genome and provided expression profiles of 44,473 transcripts in seed tissues at different developmental stages and under optimal and stress conditions. Time-course and pairwise comparisons between optimal and stress conditions showed that 9182, 8315 and 3481 genes were differentially expressed due to heat stress in embryo, endosperm and seed coat respectively. Moreover, it highlighted a common set of 975 genes that were differentially expressed in all the seed tissues.

Genome-wide association study identified candidate genes for seed size and seed composition improvement in M. truncatula.

Grain legumes are highly valuable plant species, as they produce seeds with high protein content. Increasing seed protein production and improving seed nutritional quality represent an agronomical challenge in order to promote plant protein consumption of a growing population. In this study, we used the genetic diversity, naturally present in Medicago truncatula, a model plant for legumes, to identify genes/loci regulating seed traits. Indeed, using sequencing data of 162 accessions from the Medicago HAPMAP collection, we performed genome-wide association study for 32 seed traits related to seed size and seed composition such as seed protein content/concentration, sulfur content/concentration. Using different GWAS and postGWAS methods, we identified 79 quantitative trait nucleotides (QTNs) as regulating seed size, 41 QTNs for seed composition related to nitrogen (i.e. storage protein) and sulfur (i.e. sulfur-containing amino acid) concentrations/contents. Furthermore, a strong positive correlation between seed size and protein content was revealed within the selected Medicago HAPMAP collection. In addition, several QTNs showed highly significant associations in different seed phenotypes for further functional validation studies, including one near an RNA-Binding Domain protein, which represents a valuable candidate as central regulator determining both seed size and composition. Finally, our findings in M. truncatula represent valuable resources to be exploitable in many legume crop species such as pea, common bean, and soybean due to its high synteny, which enable rapid transfer of these results into breeding programs and eventually help the improvement of legume grain production.

Novel SOD1 monoclonal antibodies against the electrostatic loop preferentially detect misfolded SOD1 aggregates.

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease that leads to motor neuron degeneration and paralysis. Superoxide dismutase (SOD1) mutations are the second most common cause of familial ALS and are responsible for up to 20 % of familial ALS cases. In ALS patients, SOD1 can form toxic misfolded aggregates that deposit in the brain and spinal cord. To better detect SOD1 aggregates and expand the repertoire of conformational SOD1 antibodies, SOD1 monoclonal antibodies were generated by immunizing SOD1 knockout mice with an SOD1 fragment consisting of amino acids 129-146, which make up part of the electrostatic loop. A series of hybridomas secreting antibodies were screened and five different SOD1 monoclonal antibodies (2C10, 2F8, 4B11, 5H5, and 5A10) were found to preferentially detect denatured or aggregated SOD1 by enzyme-linked immunosorbent assay (ELISA), filter trap assay, and immunohistochemical analysis in SOD1 mouse models. The staining with these antibodies was compared to Campbell-Switzer argyrophilic reactivity of pathological inclusions. These new conformational selective SOD1 antibodies will be useful for clinical diagnosis of SOD1 ALS and potentially for passive immunotherapy.